Reciprocal regulation of cellular nitric oxide formation by nitric oxide synthase and nitrite reductases

Our mini-review focuses on dual regulation of cellular nitric oxide (NO) signaling pathways by traditionally characterized enzymatic formation from L-arginine via the actions of NO synthases (NOS) and by enzymatic reduction of available cellular nitrite pools by a diverse class of cytosolic and mitochondrial nitrite reductases. Nitrite is a major metabolic product of NO and is found in all cell and tissue types that utilize NO signaling processes. Xanthine oxidoreductase (XOR) has been previously characterized as a housekeeping enzyme responsible for cellular uric acid formation via enzymatic conversion of hypoxanthine and xanthine. It has become apparent that XOR possesses multi-functional enzymatic activities outside the realm of xanthine metabolism and a small but significant literature also established a compelling functional association between administered sodium nitrite, XOR activation, and pharmacologically characterized NO transductive effects in positive cardiovascular function enhanced pulmonary perfusion, and protection against ischemia/reperfusion injury and hypoxic damage and oxidative stress. Similar positive vascular and cellular effects were observed to be functionally associated with mitochondrial aldehyde dehydrogenase and cytochrome c/cytochrome c oxidase. The profound implications of a reciprocal regulatory mechanism responsible for cytosolic and mitochondrial NO production are discussed below.